Endocrine Abstracts

Introduction: In recent years a growing number of gene mutations have been identified which cause a myriad of syndromes having adrenal insufficiency as a core characteristic. The evolution of each syndrome is dependent on the variant and the particular gene affected. Common practice is for candidate genes to be sequenced individually, which can be time consuming and is complicated by overlapping clinical phenotypes. The increasing availability and cost effectiveness of whole exome sequencing (WES) is proving to be a powerful alternative, especially in disorders where a large number of causative genes need to be sequenced to gain a definitive diagnosis.

Methods: WES was performed on 38 probands referred to our unit with a clinical diagnosis of familial glucocorticoid deficiency. All had been screened for mutations in MC2R, MRAP and STAR and most for mutations in GPX1 and NNT, the five genes linked to FGD.

Results: We made a genetic diagnosis in 14 probands plus two of their affected siblings, identifying mutations in the following genes; NR0B1 in four patients, CYP11A1 in five patients plus a sibling, AAAS in two patients, MC2R in one patient, CYP11B1 in one patient and AIRE in a pair of brothers, most mutations were novel. Genetic diagnoses were confirmed by direct sanger sequencing of the index case and other family members.

Conclusion: A genetic diagnosis was therefore readily achieved more than a third of patients that underwent WES. It is feasible that many of the other cases are caused by novel gene defects. WES as a diagnostic tool offers rapid accurate screening for disease variants, thus reducing erroneous clinical diagnoses and enabling targeted treatment plans that should result in better long-term clinical outcomes. We believe that the evolution of WES into a diagnostic tool offers a rapid cost effective way of screening patients for monogenic diseases.